Faculty of Biotechnology, Atma Jaya Catholic University of Indonesia, Jakarta 12930, Indonesia Email: Original Article STRUCTURE-BASED DESIGN OF NOVEL RILPIVIRINE ANALOGUES AS HIV-1 NON- NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS THROUGH QSPR AND MOLECULAR DOCKING VIVITRI D. PRASASTY*, ADI YULANDI vivitri.dewi@atmajaya.ac.id Received: 19 Mar 2015 Revised and Accepted: 05 Oct 2015 ABSTRACT Objectives: The aim of this research is to investigate the better biological activities from Rilpivirine analogues based on their Quantitative Structure-Property Relationship (QSPR) and pharmacophore study. Methods: In this study, we had designed six Rilpivirine analogues. The complementary aided-computational drug design and molecular docking was employed to find the best lead candidate. The drug-likeness properties of Rilpivirine analogues were defined by following the Rule of Five. Results: The drug-likeness properties of Rilpivirine derivatives (RVN 1-6) were defined by the Rule of Five (RO5), which RVN3 compound showed the best RO5 score among others. However, the log P value of RVN1 and RVN4 are lower than 5, while RVN2, RVN3, RVN5 and RVN6 have log P values greater than 5. Based on the solubility, RVN1 and RVN4 compounds are more soluble than other analogues including Rilpivirine prototype (RVN). The topological polar surface area (TPSA) score of RVN1 and RVN4 showed greater scores compared to others. On the other hand, the TPSA score of all Rilpivirine analogues are below 140 Å 2 . The absorption, distribution, metabolism, and excretion (ADME) properties of Rilpivirine analogues were determined, according to blood brain barrier penetration were found within the range of-1.2 to-2.2, which RVN4 showed the lowest value compared to others, while RVN showed the highest value. The percentage of human intestinal absorption was observed 100% to all compounds. The plasma protein binding percentages was obtained within the range 99.03-99.57%. Moreover, the hydrogen bond donor contribution of all compounds was in the range 2-4 bonds, while the acceptor hydrogen bond was found 6 bonds from all compounds. The mutagenicity properties showed all compounds could cause mutagenic effect in long-term administration. The carcinogenicity tests were done in mouse showed positive results to all compounds, while carcinogenicity test in rat showed negative results upon all compound, except RVN3 which gave positive result. From molecular docking result, RVN 1 and RVN 4 showed higher potential inhibition activities to Reverse Transcriptase Human Immunodeficiency Virus Type 1 (HIV-1 RT) compared other analogues. Conclusion: Non-nucleoside reverse transcriptase inhibitors (NNRTIs) have a great potential inhibition against HIV-1 RT. From high throughput computational approach, we suggested that RVN 1 and RVN 4 are the potential drug candidates which have better activity among other Rilpivirine derivatives. Keywords: NNRTIs, Rilpivirine analogues, HIV-1 RT, QSPR, Molecular docking. INTRODUCTION Reverse transcriptase (RT) of the Human Immunodeficiency Virus Type 1 (HIV-1) is an enzyme which has the critical role to viral replication in the infected host cell. HIV-1 RT consists of two subunits, p66 (66 kDa) subunit and p51 (51 kDa) subunit. The p66 subunit of HIV-1 RT acts two main roles: as DNA polymerase that reverse transcripts the single strand of RNA into the double strand of DNA, and as an endonucleolytic ribonuclease H (RNase H) that degrades the RNA from hybrid DNA. The p51 subunit of RT has only structural function. Based on its substantial role in the HIV-1 life- cycle, RT becomes a primary target for anti-HIV-1 agents. To date, the anti-HIV-1 drugs against HIV-1 RT are progressively developed. The Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) are known as antiretroviral drugs inhibit the HIV-1 infection. NNRTIs are chemically different from the common nucleosides which are not involved in the intracellular metabolism for its activity. In general, NNRTIs are a group of small hydrophobic compounds (less than 600 Da) with various structure forms that particularly inhibit HIV-1. NNRTI derivatives can be broadly categorized into first-and second- generation compounds [1]. The first generation NNRTIs, such as nevirapine, delavirdine, TIBO, and loviride (α-anilino- phenylacetamido (α-APA)), were mainly discovered by random screening and are associated with the rapid development of drug resistance mutations. The second generation NNRTIs, which including efavirenz, the quinoxaline talviraline (HBY-097), the Imidazole Capravirine, and Rilpivirine (TMC278) were developed as a result of comprehensive strategies involving molecular modeling, rationale-based drug synthesis and biological and pharmacokinetic evaluations. Second generation NNRTIs tend to be more potent than the first generation compounds, and in general are more active against a broader spectrum of drug-resistant strains of HIV-1 [1-4]. Rilpivirine (diarylpyrimidine, DPAY, trade name: Edurant) is a Non Nucleoside Reverse Transcriptase Inhibitor (NNRTI) which is approved for treatment of HIV-1 infection in antiretroviral-naive adult patients [5, 6]. Rilpivirine acts at the hydrophobic position near the NNRTI-binding site, resulting inactivation of the HIV-1 RT and terminating the HPV DNA synthesis [7]. Rilpivirine was selected for further study due to this compound is able to bind and inhibit the wild type of HIV-1 RT and a number of clinically relevant NNRTI-resistant variants. This ability derives from the geometrical flexibility of the compound within the HIV-1 RT binding pocket [8]. Further investigation of the Rilpivirine remains crucial role due to their activity against a wide range of drug-resistant variants, therefore it plays an important highly active antiretroviral therapy (HARRT) [9]. In our study, we utilize high throughput computational approach to design and analyze Rilpivirine analogues to overcome the rapid emergence of different type strain mutations which lead drug resistant by HIV-1 RT. MATERIALS AND METHODS Protein structure preparation The 3D crystal structure of RT-Rilpivirine complex was extracted from Protein Data Bank (PDB ID 2ZD1). Subunit p66 was used in this International Journal of Pharmacy and Pharmaceutical Sciences ISSN- 0975-1491 Vol 7, Issue 11, 2015 Innovare Academic Sciences